Palladium-Catalyzed C-H Olefination of Imidazo[1,2a] pyridine Carboxamide in Aqueous Ethanol under Oxygen.

The advancement of sustainable chemistry and changes in the economy are strongly intertwined. Reaction time, cost savings, moderate temperatures, and generation of the fewest byproducts are frequently achieved by using catalytic processes. Herein, we report the C-H olefination of imidazo[1,2a] pyridine carboxamides with various acrylates in the presence of Pd (OAc)2 with O2 as the oxidant in aqueous ethanol rather than using non-ecofriendly solvents. The C-H activation features most user-friendly reaction conditions, excellent yield as well as plenty substrate scope and applicable for C-H deuteriation of the corresponding heteroarenes with D2O. Experimental mechanistic studies indicate that C-H activation step succeeded after formation of tetra coordinated square planer Pd-substrate adduct.

Key challenges in TB drug discovery: A perspective.

Over the past 2000 years, tuberculosis (TB) has been responsible for more deaths than any other infectious disease. In recent years, there has been a recovery of research and development (R&D) efforts focused on TB drugs. This is driven by the pressing need to combat the global spread of the disease and develop improved therapies for both drug-sensitive and drug-resistant strains. Many new TB drug candidates have recently entered clinical trials, marking the beginning of a rebirth in this area after decades of neglect. The problem is that very few of the hundreds of compounds identified each year as potential anti-TB drugs really make it to the clinical development stage. This perspective focuses on the primary obstacles and approaches involved in the development of new medications for TB. This will help medicinal chemists better understand TB drug challenges and develop novel drug candidates.

Exploring the Recent Pioneering Developments of Small Molecules in Antimalarial Drug Armamentarium: A Chemistry Prospective Appraisal.

Malaria is a very destructive and lethal parasitic disease that causes significant mortality worldwide, resulting in the loss of millions of lives annually. It is an infectious disease transmitted by mosquitoes, which is caused by different species of the parasite protozoan belonging to the genus Plasmodium. The uncontrolled intake of antimalarial drugs often employed in clinical settings has resulted in the emergence of numerous strains of plasmodium that are resistant to these drugs, including multidrug-resistant strains. This resistance significantly diminishes the effectiveness of many primary drugs used in the treatment of malaria. Hence, there is an urgent need for developing unique classes of antimalarial drugs that function with distinct mechanisms of action. In this context, the design and development of hybrid compounds that combine pharmacophoric properties from different lead molecules into a single unit gives a unique perspective towards further development of malaria drugs in the next generation. In recent years, the field of medicinal chemistry has made significant efforts resulting in the discovery and synthesis of numerous small novel compounds that exhibit potent antimalarial properties, while also demonstrating reduced toxicity and desirable efficacy. In light of this, we have reviewed the progress of hybrid antimalarial agents from 2021 up to the present. This manuscript presents a comprehensive overview of the latest advancements in the medicinal chemistry pertaining to small molecules, with a specific focus on their potential as antimalarial agents. As possible antimalarial drugs that might target both the dual stage and multi-stage stages of the parasite life cycle, these small hybrid molecules have been studied. This review explores a variety of physiologically active compounds that have been described in the literature in order to lay a strong foundation for the logical design and eventual identification of antimalarial drugs based on lead frameworks.

Palladium-Catalyzed Regiodivergent C-H Olefination of Imidazo[1,2a]pyridine Carboxamide and Unactivated Alkenes.

Despite remarkable successes in linear and branched vinyl (hetero) arene synthesis, regiodivergent C-H olefination with a single catalytic system has remained underdeveloped. Overcoming this limitation, a Pd/MPAA-catalyzed regiodivergent C-H olefination of imidazo[1,2a] pyridine carboxamides with unactivated terminal alkenes to generate branched and linear olefinated products depending upon the electronic nature of alkenes is reported herein. Moreover, this protocol can be applied for C-H deuteriation of the corresponding heteroarenes with D2 O as deuterium source. Preliminary experimental studies combined with computational investigations (DFT studies) suggest that regiodivergent olefination can be controlled by olefin insertion and ß-hydride elimination steps.

A concise review on marine bromopyrrole alkaloids as anticancer agents.

Natural products have been the most important sources of chemically diverse raw materials that have inspired pharmaceutical discoveries over the past few decades. Many pharmaceutical companies are utilizing plant extracts to develop relatively crude therapeutic formulations. The interesting chemicals identified as natural products are derived from the phenomenon of biodiversity, where the interactions between the organisms and their environment formulate the diverse and complex chemical entities within them that enhance their survival and competitiveness. Marine sponges are rich sources of natural products and have provided an infinite supply of bioactive metabolites. Bromopyrrole alkaloids are a good example of marine metabolites, have a broad range of biological activity, and represent a fascinating example of chemical diversity of secondary metabolites elaborated by marine invertebrates. The isolation and synthesis of this structural class have been investigated, resulting in a series of bromopyrrole alkaloids with potential lead hits. This review presents the detailed isolation and anticancer activity of marine bromopyrrole alkaloids, and will be of interest to the wider research community both in academic and industrial settings.

Recent progress in electrochemical sensors for detection and quantification of malaria.

Malaria is still a major disease in sub-Saharan Africa and South-East Asia. This is despite different interventions by the World Health Organization (WHO), such as insecticide-treated mosquito net, antimalarial drugs, indoor residual spraying, and rapid diagnostic tools. In 2018, the mortality rate due to malaria was estimated to be 405 000, with children under five years accounting for 67% of all malaria deaths. Malaria can be prevented and treated using different strategies as recommended by WHO. However, the lack of rapid diagnostic tools with good selectivity and sensitivity is still a challenge. Therefore there is a need to develop rapid, low-cost, and portable analytical methods for quantifying malaria. This review focuses on the role of malaria biomarkers (Plasmodium falciparum Lactate Dehydrogenase (PfLDH), Plasmodium aldolase, Plasmodium falciparum Histidine-Rich Protein 2 (PfHRP2), Plasmodium falciparum Glutamate dehydrogenase (PfGDH), and Hemozoin) in diagnosis. Recent developments in nanomaterial-based electrochemical and colorimetric biosensors for malaria diagnosis are discussed. Finally, the review concludes with closing remarks and future perspectives of electrochemical biosensors.

Cu-catalysed transamidation of unactivated aliphatic amides.

Direct transamidation is gaining prominence as a ground-breaking technique that generates a wide variety of amides without the requirement of acid-amine coupling or other intermediate steps. However, transamidation of unactivated aliphatic amides, on the other hand, has been a long-standing issue in comparison to transamidation of activated amides. Herein, we report a transamidation approach of an unactivated aliphatic amide using a copper catalyst and chlorotrimethylsilane as an additive. In addition, we used transamidation as a tool for selective N-C(O) cleavage and O-C(O) formation to synthesise 2-substituted benzoxazoles and benzothiazoles. The reactions were carried out without using any solvents and offered wide substitution scope.

An Overview on Synthetic and Medicinal Perspectives of [1,2,4]Triazolo[1,5-a]pyrimidine Scaffold.

[1,2,4]Triazolo[1,5-a]pyrimidine is an important heterocyclic scaffold known to have a wide range of pharmacological activities such as anticancer, antimicrobial, anti-tubercular, CB2 cannabinoid agonists, feticide, and adenosine antagonists. Several clinical trials and marketed drugs such as Trapidil, Essramycin, Pyroxsulam, DSM-265, Flumetsulam, GNF-6702, and Cevipabulin indicate the potential of [1,2,4]triazolo[1,5-a]pyrimidine moiety with various functional groups in medicinal chemistry. Herein, we represent a concise report focusing on the synthetic strategies used for diversely substituted [1,2,4]triazolo[1,5-a]pyrimidine analogs and their pharmacological applications. To the best of our knowledge, since 1980, we are the first to write a review on this emerging scaffold, which reveals the synthetic strategies, and pharmacological activities of differently substituted [1,2,4]triazolo[1,5-a]pyrimidine with special emphasis on structure-activity relationship studies.

Lifestyles Shape the Cytochrome P450 Repertoire of the Bacterial Phylum Proteobacteria.

For the last six decades, cytochrome P450 monooxygenases (CYPs/P450s), heme thiolate proteins, have been under the spotlight due to their regio- and stereo-selective oxidation activities, which has led to the exploration of their applications in almost all known areas of biology. The availability of many genome sequences allows us to understand the evolution of P450s in different organisms, especially in the Bacteria domain. The phenomenon that "P450s play a key role in organisms' adaptation vis a vis lifestyle of organisms impacts P450 content in their genome" was proposed based on studies on a handful of individual bacterial groups. To have conclusive evidence, one must analyze P450s and their role in secondary metabolism in species with diverse lifestyles but that belong to the same category. We selected species of the phylum Proteobacteria classes, Alpha, Beta, Gamma, Delta, and Epsilon, to address this research gap due to their diverse lifestyle and ancient nature. The study identified that the lifestyle of alpha-, beta-, gamma-, delta-, and epsilon-proteobacterial species profoundly affected P450 profiles in their genomes. The study determined that irrespective of the species associated with different proteobacterial classes, pathogenic species or species adapted to a simple lifestyle lost or had few P450s in their genomes. On the contrary, species with saprophytic or complex lifestyles had many P450s and secondary metabolite biosynthetic gene clusters. The study findings prove that the phenomenon mentioned above is factual, and there is no link between the number and diversity of P450s and the age of the bacteria.

Lactate dehydrogenase and malate dehydrogenase: Potential antiparasitic targets for drug development studies.

Parasitic diseases remain a major public health concern for humans, claiming millions of lives annually. Although different treatments are required for these diseases, drug usage is limited due to the development of resistance and toxicity, which necessitate alternative therapies. It has been shown in the literature that parasitic lactate dehydrogenases (LDH) and malate dehydrogenases (MDH) have unique pharmacological selective and specificity properties compared to other isoforms, thus highlighting them as viable therapeutic targets involved in aerobic and anaerobic glycolytic pathways. LDH and MDH are important therapeutic targets for invasive parasites because they play a critical role in the progression and development of parasitic diseases. Any strategy to impede these enzymes would be fatal to the parasites, paving the way to develop and discover novel antiparasitic agents. This review aims to highlight the importance of parasitic LDH and MDH as therapeutic drug targets in selected obligate apicoplast parasites. To the best of our knowledge, this review presents the first comprehensive review of LDH and MDH as potential antiparasitic targets for drug development studies.

Novel thiomorpholine tethered isatin hydrazones as potential inhibitors of resistant Mycobacterium tuberculosis.

Novel chemotherapeutic agents against multidrug resistant-tuberculosis (MDR-TB) are urgently needed at this juncture to save the life of TB-infected patients. In this work, we have synthesized and characterized novel isatin hydrazones 4(a-o) and their thiomorpholine tethered analogues 5(a-o). All the synthesized compounds were initially screened for their anti-mycobacterial activity against the H37Rv strain of Mycobacterium tuberculosis (MTB) under level-I testing. Remarkably, five compounds 4f, 4h, 4n, 5f and 5m (IC50 = 1.9 µM to 9.8 µM) were found to be most active, with 4f (IC50 = 1.9 µM) indicating highest inhibition of H37Rv. These compounds were further evaluated at level-II testing against the five drug-resistant strains such as isoniazid-resistant strains (INH-R1 and INH-R2), rifampicin-resistant strains (RIF-R1 and RIF-R2) and fluoroquinolone-resistant strain (FQ-R1) of MTB. Interestingly, 4f and 5f emerged as the most potent compounds with IC50 of 3.6 µM and 1.9 µM against RIF-R1 MTB strain, followed by INH-R1 MTB strain with IC50 of 3.5 µM and 3.4 µM, respectively. Against FQ-R1 MTB strain, the lead compounds 4f and 5f displayed excellent inhibition at IC50 5.9 µM and 4.9 µM, respectively indicating broad-spectrum of activity. Further, molecular docking, ADME pharmacokinetic and molecular dynamics simulations of the compounds were performed against the DNA gyrase B and obtained encouraging results.

Design and synthesis of pyrazolone-based compounds as potent blockers of SARS-CoV-2 viral entry into the host cells.

SARS-CoV-2 are enveloped positive-stranded RNA viruses that replicate in the cytoplasm. It relies on the fusion of their envelope with the host cell membrane to deliver their nucleocapsid into the host cell. The spike glycoprotein (S) mediates virus entry into cells via the human Angiotensin-converting enzyme 2 (hACE2) protein located on many cell types and tissues' outer surface. This study, therefore, aimed to design and synthesize novel pyrazolone-based compounds as potential inhibitors that would interrupt the interaction between the viral spike protein and the host cell receptor to prevent SARS-CoV 2 entrance into the cell. A series of pyrazolone compounds as potential SARS-CoV-2 inhibitors were designed and synthesized. Employing computational techniques, the inhibitory potentials of the designed compounds against both spike protein and hACE2 were evaluated. Results of the binding free energy from the in-silico analysis, showed that three compounds (7i, 7k and 8f) and six compounds (7b, 7h, 7k, 8d, 8g, and 8h) showed higher and better binding high affinity to SARS-CoV-2 Sgp and hACE-2, respectively compared to the standard drugs cefoperazone (CFZ) and MLN-4760. Furthermore, the outcome of the structural analysis of the two proteins upon binding of the inhibitors showed that the two proteins (SARS-CoV-2 Sgp and hACE-2) were stable, and the structural integrity of the proteins was not compromised. This study suggests pyrazolone-based compounds might be potent blockers of the viral entry into the host cells.

One-Pot, Multicomponent, Diastereoselective, Green Synthesis of 3,4-Dihydro-2H-benzo[b][1,4]oxazine Analogues.

A novel green and efficient catalyst-free, mild one-pot, multicomponent synthetic strategy has been developed to construct substituted 3,4-dihydro-2H-benzo[b][1,4]oxazine. This reaction proceeds via in situ formation of Schiff-base followed by base mediated alkylation with phenacyl bromide/substituted phenacyl bromide, finally leading to intramolecular cyclization to give a mixture of diastereomers with excellent diastereoselectivity (up to dr = 99:1), which were isolated as a single diastereomer in moderate to excellent yields (41-92%). Besides, this new versatile methodology provides a wide scope for the synthesis of different functionally substituted benzoxazine scaffolds and can be further exploited as building blocks for the synthesis of multifaceted molecular structures, especially for pharmaceutical applications.

Exploring MDR-TB Inhibitory Potential of 4-Aminoquinazolines as Mycobacterium tuberculosis N-Acetylglucosamine-1-Phosphate Uridyltransferase (GlmUMTB ) Inhibitors.

Drug resistance tuberculosis is one of the challenging tasks that dictates the desperate need for the development of new antitubercular agents which operate via novel modes of action. Here, we are reporting on 4-aminoquinazolines as M. tuberculosis N-acetylglucosamine-1-phosphate uridyltransferase (GlmUMTB ) inhibitors to overcome the problem of the MDR-TB. Amongst the synthesized compounds, two of them were observed to be the effective compounds of the series (IC50 =6.4 µM (H37Rv), MIC=25 µM (MDR-TB) and IC50 =2.9 µM (H37Rv), MIC=6.25 µM (MDR-TB), respectively).

Synthesis and Biological Evaluation of Novel Carbazole Hybrids as Promising Antimicrobial Agents.

Two series of carbazole analogs of 8-methoxy-N-substituted-9H-carbazole-3-carboxamides (series 1) and carbazolyl substituted rhodanines (series 2) were synthesized through facile synthetic routes. All the final compounds from these two series were evaluated for their preliminary in vitro antifungal and antibacterial activity against four fungal (Candida albicans, Cryptococcus neoformans, Cryptococcus tropicalis and Aspergillus niger) and four bacterial (Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa) strains, respectively. Among the tested compounds, three compounds of series 1 displayed promising antifungal and antibacterial activity, especially against C. neoformans and S. aureus. In addition, one compound of series 1 displayed notable antimicrobial activity (MIC: 6.25 µg/mL) against clinical isolates of C. albicans and C. neoformans (MIC: 12.5 µg/mL). From the second series, four compounds exhibited significant antifungal and antibacterial activity, especially against C. neoformans and S. aureus. The most active compound of series 2 displayed a prominent antimicrobial activity against C. neoformans (MIC: 3.125 µg/mL) and S. aureus (MIC: 1.56 µg/mL), respectively.

A poly(acrylic acid)-modified copper-organic framework for electrochemical determination of vancomycin.

A copper(II) benzene-1,3,5-tricarboxylate (BTC) metal-organic framework (MOF) was modified with poly(acrylic acid) (PAA) and then used in an electrochemical sensor for vancomycin. The MOF, synthesized via a single-pot method, has enhanced solubility and dispersibility in water as compared to HKUST-1 but without compromising its crystallinity and porosity. The MOF was placed on a glassy carbon electrode (GCE) where it shows enhanced electrocatalytic properties. This is assumed to be due to the presence of the poly(acrylic acid) that forms a network between various HKUST-1 crystals through dimer formation between the carboxy groups of BTC and PAA. This also led to better dispersion of the MOF and to improved interaction between MOF and vancomycin. The structural, spectral and electrochemical properties of the MOFs and their vancomycin complexes was characterized. The modified GCE is shown to be a viable tool for electrochemical determination (best at a working potential of 784 mV vs. Ag/AgCl) of the antibiotic vancomycin in spiked urine and serum samples. Response is linear in the 1-500 nM vancomycin concentration range, and the detection limit is 1 nM, with a relative standard deviation of ±4.3%. Graphical abstractSchematic representation of a method for determination of vancomycin. Poly(acrylic acid) modified HKUST-1 (P-HKUST-1) forms a complex with vancomycin [Van-P-HKUST-1] which is coated over glassy carbon electrode (GCE). The decrease in peak current is recorded as response to vancomycin via cyclic voltammetry.

Alkaloids with Anti-Onchocercal Activity from Voacanga africana Stapf (Apocynaceae): Identification and Molecular Modeling.

A new iboga-vobasine-type isomeric bisindole alkaloid named voacamine A (1), along with eight known compounds-voacangine (2), voacristine (3), coronaridine (4), tabernanthine (5), iboxygaine (6), voacamine (7), voacorine (8) and conoduramine (9)-were isolated from the stem bark of Voacangaafricana. The structures of the compounds were determined by comprehensive spectroscopic analyses. Compounds 1, 2, 3, 4, 6, 7 and 8 were found to inhibit the motility of both the microfilariae (Mf) and adult male worms of Onchocerca ochengi, in a dose-dependent manner, but were only moderately active on the adult female worms upon biochemical assessment at 30 µM drug concentrations. The IC50 values of the isolates are 2.49-5.49 µM for microfilariae and 3.45-17.87 µM for adult males. Homology modeling was used to generate a 3D model of the O. ochengi thioredoxin reductase target and docking simulation, followed by molecular dynamics and binding free energy calculations attempted to offer an explanation of the anti-onchocercal structure-activity relationship (SAR) of the isolated compounds. These alkaloids are new potential leads for the development of antifilarial drugs. The results of this study validate the traditional use of V. africana in the treatment of human onchocerciasis.

Discovery of novel N-methyl carbazole tethered rhodanine derivatives as direct inhibitors of Mycobacterium tuberculosis InhA.

InhA (Enoyl-ACP reductase) plays a crucial role in the biosynthetic pathway of cell wall synthesis in Mycobacterium tuberculosis (Mtb). Isoniazid (INH) is an important first-line drug, which inhibits InhA. The rapid increase in resistance to INH and currently marketed drugs as well as emergence of MDR-TB and XDR-TB has complicated the diagnosis and treatment of Mtb with ever increasing threat to human kind. Herein, we report novel N-methyl carbazole derivatives as potential anti-TB compounds acting directly via InhA inhibition. All the synthesized final compounds were screened against Mtb virulent cell line H37Rv and investigated the InhA enzyme inhibition. Interestingly, compound 9e displayed promising inhibition (91%) at 50 µM concentration and IC50 of 2.82 µM against InhA. To understand the ligand receptor interaction between compound 9e and InhA, molecular docking and molecular dynamics experiments were performed. The computational results were in agreement with the observed experimental data. Further, the cytotoxicity studies on mammalian cells revealed that all the compounds were safe.

Nanomaterial-based optical and electrochemical techniques for detection of methicillin-resistant Staphylococcus aureus: a review.

Methicillin-resistant Staphylococcus aureus (MRSA) is responsible for a number of life-threatening complications in humans. Mutations in the genetic sequence of S. aureus due to the presence of certain genes results in resistance against ß-lactamases. Thus, there is an urgent need for developing highly sensitive techniques for the early detection of MRSA to counter the rise in resistant strains. This review (142 refs.) extensively covers literature reports on nanomaterial-based optical and electrochemical sensors from the year 1983 to date, with particularly emphasis on recent advances in electrochemical sensing (such as voltammetry and impedimetric) and optical sensing (such as colorimetry and fluorometry) techniques. Among the electrochemical methods, various nanomaterials were employed for the modification of electrodes. Whereas, in optical assays, formats such as enzyme linked immunosorbent assay, lateral flow assays or in optical fiber systems are common. In addition, novel sensing platforms are reported by applying advanced nanomaterials which include gold nanoparticles, nanotitania, graphene, graphene-oxide, cadmium telluride and related quantum dots, nanocomposites, upconversion nanoparticles and bacteriophages. Finally, closing remarks and an outlook conclude the review. Graphical abstract Schematic of the diversity of nanomaterial-based methods for detection of methicillin-resistant Staphylococcus aureus (MRSA). AuNPs: gold nanoparticles; QDs: quantum dots; PVL: Panton-Valentine leukocidin; mecA gene: mec-gene complex encoding methicillin resistance.

Cytochrome P450 Monooxygenase CYP139 Family Involved in the Synthesis of Secondary Metabolites in 824 Mycobacterial Species.

Tuberculosis (TB) is one of the top infectious diseases causing numerous human deaths in the world. Despite enormous efforts, the physiology of the causative agent, Mycobacterium tuberculosis, is poorly understood. To contribute to better understanding the physiological capacity of these microbes, we have carried out extensive in silico analyses of the 1111 mycobacterial species genomes focusing on revealing the role of the orphan cytochrome P450 monooxygenase (CYP) CYP139 family. We have found that CYP139 members are present in 894 species belonging to three mycobacterial groups: M. tuberculosis complex (850-species), Mycobacterium avium complex (34-species), and non-tuberculosis mycobacteria (10-species), with all CYP139 members belonging to the subfamily "A". CYP139 members have unique amino acid patterns at the CXG motif. Amino acid conservation analysis placed this family in the 8th among CYP families belonging to different biological domains and kingdoms. Biosynthetic gene cluster analyses have revealed that 92% of CYP139As might be associated with producing different secondary metabolites. Such enhanced secondary metabolic potentials with the involvement of CYP139A members might have provided mycobacterial species with advantageous traits in diverse niches competing with other microbial or viral agents, and might help these microbes infect hosts by interfering with the hosts' metabolism and immune system.